Over 50,000 papers have been published on the amyloid- peptide (A) that collects in the brains of patients with Alzheimer's disease (AD), leading to numerous theories that have two points in common: (1) A is thought to be toxic by chemical and physical means, such as metal binding, reactive oxygen species production, and membrane damage; (2) the physiological function of this widely-produced peptide is unknown. We have produced transgenic mice with numerous plaques and high levels of A40 and 42, yet no behavioral abnormalities, electrophysiological abnormalities, synaptic loss, or dentate gyral atrophy (Galvan et al., 2006; Saganich et al., 2006). Our results suggest an alternative view of Alzheimer's disease as an imbalance in physiological signaling-specifically, between the signaling involved in neurite extension and that involved in neurite retraction, both mediated by APP (amyloid precursor protein). We have identified alternative ligands for APP that mediate these two antagonistic effects: netrin-1 binds APP and supports neurite extension (Lourenco et al., 2009), whereas A competes with netrin-1 for APP and mediates neurite retraction (Lu et al., 2003; Shaked et al., 2006). These results also suggest a physiological role for A, as an anti-trophin that competes with netrin-1 and mediates physiological neurite retraction and cell death. We have begun to dissect the downstream network that mediates the resulting AD phenotype. We have developed and utilized TAIS (target-assisted iterative screening), a rapid approach to the identification of novel protein-protein interactors (Kurakin and Bredesen, 2002; Kurakin et al., 2003), to identify 40 proteins that interact with the PDZ domain tandem of the APP interactor Mint/X11 family proteins. These proteins provide new insights into the mechanisms underlying the AD phenotype (Galvan et al., 2006; Swistowski et al., 2009). Interestingly, 14 of the 40 proteins identified are transcriptional regulators, suggesting that, jut as the tripartite complex AICD-Fe65-Tip60 may be involved in transcription (Cao and Sudhof, 2001; Baek et al., 2002), transcriptional complexes mediating APP signaling may also include Mint/X11 proteins and their interacting transcriptional regulators. These results also reveal new potential therapeutic targets. Our long-term goal is to obtain a comprehensive mechanistic understanding of intracellular signaling pathways that mediate Alzheimer's disease, revealing new therapeutic targets. PUBLIC HEALTH RELEVANCE: Our long-term goal is to obtain a comprehensive mechanistic understanding of intracellular signaling pathways that mediate Alzheimer's disease, revealing new therapeutic targets.